. This proposal discusses the development of small molecule, orally active antimicrobial agents acting by modulation of bacterial transcription. Novel antibiotics disrupting transcription are likely to overcome important limitations of existing antibiotics because of reduced development of resistance. Although bacterial infections were considered well controlled, the threat posed by the emergence of multidrug-resistant organisms is now apparent. Transcription-targeted therapy offers new targets that are now addressed by existing antibiotics. Choosing transcription targets that represent multigene families will reduce the rate at which resistance emerges. Established high throughput in vitro assays at SCRIPTGEN have uncovered a class of molecules that inhibit bacterial transcription specifically. Medicinal chemistry for this program has begun and analogs of increased potency and specificity have been prepared. Secondary screens indicate that some analogs exhibit thousand fold specificity for inhibition of pathogenic bacterial RNA polymerases versus human RNA polymerase. The molecules are arylhydrazones whose structure and ease of analog preparation make them highly amenable to a medicinal chemistry program. Arylhydrazones possess structural features that make them less than optimal drug candidates. Structural modifications to increase potency, specificity, and bioavailability, while attenuating toxicity are proposed.